PROJECT SUMMARY Pancreatic cancer is a devastating disease that is refractory to standard chemotherapies, as demonstrated by the low five-year survival rate of 6%. The objective of this proposal is to clinically evaluate a novel therapeutic for the treatment of pancreatic cancer with in order to improve survival rates The sigma-2 (S2) receptor is overexpressed in pancreatic cancer, and small molecule ligands to this receptor localize to these tumors. In addition, PDAC cancer cells rapidly internalize selected sigma-2 ligands. This finding prompted us to explore the possibility of using these ligands to deliver a therapeutic payload to PDAC tumor cells via chemical linkage with our ligands. We have successfully used S2 ligands to deliver structurally diverse compounds including both peptides and small molecule therapeutics (classic chemotherapeutics [rapamycin] and peptidomimetics), into the cancer cells both in vitro and in vivo. In each case, the activity profiles of the conjugates were far greater than the isolated components or their equimolar combinations. Based on this delivery mechanism, we combined the tumor selectivity of the S2 ligand with a promising drug cargo that induces cell death selectively in PDAC, to create a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer tumor models with limited systemic toxicity. This project will perform pharmacology and toxicity assays, and test the conjugate in a clinical trial.